The term "solvent system" as used herein refers to a carrier in which an active drug (i.e. a cyclosporin) is dissolved. The solvent system may be a single solvent or a mixture of ingredients included as solvents, surfactants, diluents, or for other purposes.
The term "cyclosporin" as used herein refers to any member of a class of nonpolar polypeptides, as defined in the Merck Index, Twelfth Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporine" and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant.
Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions (i.e. dosage forms) comprising cyclosporins which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration.
The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous medium, the cyclosporin will precipitate.
Methods of overcoming this problem are now known in the prior art. The most common approach is to dissolve the cyclosporin in a solvent system that comprises at least one lipophilic (hydrophobic) solvent and a surfactant, so that the composition disperses into an emulsion when mixed into gastrointestinal fluid or other aqueous medium.
Such compositions are called "emulsion preconcentrates".
U.S. Pat. No. 4,388,307 discloses such compositions. A commercial product that has been sold under the trademark "Sandimmune" is made according to U.S. Pat. No. 4,388,307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol as hydrophilic solvent, a vegetable oil as lipophilic solvent, and a surfactant. The ethanol is required to dissolve the cyclosporin in the composition as the vegetable oil has inadequate capacity to dissolve cyclosporins. While this composition is superior to previously known compositions, it still exhibits absorption that is less than the maximum possible and is variable. Moreover, the use of ethanol has disadvantages, as ethanol is volatile, and Sandimmune capsules must be individually packaged in metallic pouches to avoid evaporation of the ethanol.
U.S. Pat. No. 5,342,625 discloses compositions that are superior in certain respects to the compositions taught in the prior reference. The compositions of U.S. Pat. No. 5,342,625 also comprise, in addition to the cyclosporin, a hydrophilic solvent, a lipophilic (i.e. hydrophobic) solvent and a surfactant. Again, the hydrophilic solvent is an alcohol and more particularly a polyol which consists of either propylene glycol or a pharmaceutically acceptable alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol. This reference teaches that only lipophilic solvent that is not miscible with the selected hydrophilic solvent is suitable for the purpose of this invention.
It is also disclosed that compositions according to U.S. Pat. No. 5,342,625, when added to water, disperse into emulsions with droplet size of less than 2000 .ANG., which is smaller than obtained with prior art compositions, thus leading to improved absorption.
Emulsions with droplet size of less than 2000 .ANG. are defined as "microemulsions". Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates".
UK Patent Application No. 2 270 842 published Mar. 30, 1994 relates to pharmaceutical compositions comprising cyclosporin in a carrier medium; the carrier comprises:
(i) a hydrophilic organic solvent in the form of a polyol and/or a lower alkanol such as propylene glycol and ethanol; PA1 (ii) a lipophilic solvent; and PA1 (iii) a polyoxyethylene-sorbitan-fatty acid ester surfactant. PA1 (i) as hydrophilic solvent, propylene glycol, either alone or with other lower alkanols e.g. ethanol; PA1 (ii) as lipophilic solvent a mixed mono-, di- and tri-glyceride; and PA1 (iii) a surfactant. PA1 1. Ethanol is volatile, so that the soft gelatin capsules have to be packaged individually in metallic pouches to prevent evaporation of the ethanol. PA1 2. Ethanol contributes to an undesirable taste of the microemulsion preconcentrate, so that, even after dilution into a sweetened drink, there is still a somewhat unpleasant taste. PA1 3. The lipophilic solvent, which is mixed mono- di- and tri-glycerides, is relatively expensive. PA1 i) vegetable oils (which are comprised primarily of fatty acid triglyercides), and extracts therefrom. PA1 ii) any of the mono- or diglycerides approved for pharmaceutical use, including, for example, glyceryl mono-oleate. PA1 iii) a mixed mono-, di-, and triglyceride, which will preferably comprise a mixture of C.sub.12-20 fatty acid mono-, di- and triglycerides. PA1 Preferably these mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C.sub.18 unsaturated fatty acid residues such as linolenic, linoleic and oleic acid residues. PA1 The mixed mono-, di-, and tri-glycerides are preferably predominantly comprised of mono- and di-glycerides. PA1 The mixed mono-, di-, and tri-glycerides may be prepared by admixing individual mono-, di, and tri-glycerides in appropriate relative proportions. Conveniently, however, the mixed glycerides comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil, soybean oil, corn oil, sunflower oil or safflower oil, with glycerol. Preferably the vegetable oil is corn oil. Also, mixtures of the oils may be transesterified with glycerol. PA1 The transesterification products are generally obtained by heating the selected vegetable oil with glycerol to effect transesterification or glycerolysis. This may be carried out at high temperature in the presence of an appropriate catalyst, under an inert atmosphere and with continuous agitation. In addition to the mono-, di- and tri-glyceride components, the transesterification products also generally comprise minor amounts of free glycerol. PA1 Transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides. An example of a suitable mixed glyceride product is the transesterification product commercially available under the trade name MAISINE (available from the company Etablissements Gattefosse, of 36 Chemin de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)). This product is comprised predominantly of linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides. PA1 iv) Acetylated monoglycerides which consist of glycerol esterified with fatty acids at one of the three hydroxyl functions, with the other two hydroxyls replaced by an acetyl moeities. PA1 Acetylated monoglycerides are sold in the United States under the tradename "Myvacet" by Eastman Chemical Products Inc. They are made by reacting fats with glycerine and triacetin. PA1 By adjusting the degree of saturation of the monoglyceride and the degree of acetylation, different characteristics are obtained. PA1 Fully acetylated monoglycerides prepared from unsaturated monoglycerides are liquids at room temperature. In this context, the phrase "fully acetylated" is intended to mean having a minimum acetylation of about 96%. PA1 Fully acetylated monoglycerides are currently available from Eastman Chemical Products Inc. under the designations Myvacet 9-08 and Myvacet 9-45. For Myvacet 9-08, the fat source is hydrogenated coconut oil. For Myvacet 9-45 the fat source is partially hydrogenated soybean oil. PA1 Myvacet 9-08 and Myvacet 9-45 are both liquids at room temperature, having melting points of 4.degree. C. to 12.degree. C. Both are well suited for use as lipophilic solvent, but Myvacet 9-45 is especially preferred because of its lower cost. PA1 1. Low cost. PA1 2. They are good solvents for cyclosporins. PA1 3. They are entirely miscible with propylene carbonate.
Canadian Patent 2072509 discloses microemulsion preconcentrates comprising a cyclosporin dissolved in a carrier which comprises:
Again the hydrophilic solvent and the lipophilic solvent are not intermiscible.
The compositions taught by Canadian Patent 2072509 appear to be within the scope of claim 1 of U.S. Pat. No. 5,342,625, but limited to propylene glycol as hydrophilic solvent and a mixed mono-, di- and tri-glyceride as lipophilic solvent.
A composition made according to the disclosure of Canadian patent 2072509 is now marketed under the trademark "Neoral", in the form of both an oral liquid which is a microemulsion preconcentrate intended to be diluted into an aqueous drink before ingestion, and a soft gelatin capsule containing the microemulsion preconcentrate.
For both the soft gelatin capsules and the oral liquid, the labelling indicates that the "Neoral" emulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil glycerides as lipophilic (hydrophobic) solvent, and polyoxyl 40 hydrogenated castor oil as surfactant. It also contains dl-alpha-tocopherol at a level of about one percent by weight as antioxidant. Although Canadian patent 2072509 includes some examples without ethanol, the use of ethanol in the commercial "Neoral" product indicates that compositions without ethanol either were not found to give adequate stability or were not found to give adequate absorption upon ingestion.
While Neoral does enable improved absorption relative to Sandimmune, it still has certain undesirable properties. Specifically:
Several prior art publications disclose further improvements achieved by selecting different lipophilic and/or hydrophilic solvents.
International Publication Number W094/25068 discloses improved compositions in the form of microemulsion preconcentrates in which the principal solvent for the cyclosporin is an alcohol which is selected from alcohols having a boiling point above 100.degree. C. and a solubility in water of under 10 g per 100 g at 20.degree. C. Because such alcohols are good solvents for cyclosporine, they eliminate the need for ethanol. Preferred alcohols, within the scope of the disclosure of W094/25068, are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including 1-octyl, 2-octyl, 1-decyl, 1-dodecyl and 1-tetradecyl alcohols. However, a problem with such compositions is that the selected alcohols are more toxic than other lipophilic solvents generally used in the art.
New Zealand Patent Application No. 280689 discloses improved microemulsion preconcentrates in which a cyclosporin is dissolved in a solvent system comprising a lipophilic (hydrophobic solvent), a hydrophilic solvent and a surfactant, wherein the lipophilic solvent is selected from tocol, tocopherols and tocotrienols, and derivatives thereof, including specifically Vitamin E.
New Zealand Patent Application No. 280689 also discloses use of propylene carbonate as hydrophilic solvent to overcome some of the problems found in the prior art compositions.
Preferred compositions within the scope of New Zealand Patent application No. 280689 comprise both a lipophilic solvent selected from tocol, tocopherols and tocotrienols and derivatives thereof, including specifically Vitamin E, and a hydrophilic solvent selected from propylene carbonate and polyethylene glycols having average molecular weight of less than 1000. In the compositions disclosed in New Zealand Patent application No. 280689, the lipophilic and hydrophilic solvents are again not intermiscible. While these compositions exhibit improved properties over the prior art, the disclosed lipophilic solvent such as Vitamin E are relatively expensive.
Accordingly, it is an object of the within invention to enable galenical formulations comprising cyclosporin which exhibit improved properties or at least perform as well as the ones taught by New Zealand Patent Application No. 280689 and which are less expensive, thus reducing the cost of therapy.